.jpg)
Outcome of sustained virological responders with histologically advanced chronic hepatitis C (Early HCV Therapy?)
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.
Sunday, August 29, 2010
Outcome of sustained virological responders with histologically advanced chronic hepatitis C.
Outcome of sustained virological responders with histologically advanced chronic hepatitis C.....(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).
Screen shot 2010-08-27 at 9.14.54 AM.png
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 × 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.
< br>
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.
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).
Screen shot 2010-08-27 at 9.14.54 AM.png
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 × 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.
< br>
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.
Survival of Hepatitis C Virus in Syringes: Implication for Transmission among Injection Drug Users
Survival of Hepatitis C Virus in Syringes: Implication for Transmission among Injection Drug Users - published pdf attached, Editorial follows
The Journal of Infectious Diseases Sept 15 2010 Early publication
"This is the first study to our knowledge to establish the survival of HCV in contaminated syringes and the duration of potential infectiousness. The finding of prolonged duration of survival of HCV in syringes is a public health concern and adds additional evidence of the need for effective syringe exchange programs and other mechanisms to expand syringe access for IDUs......In our experimental simulation of IDU injection practices, we observed that HCV survived in HCV‐contaminated syringes for up to 63 days in high void volume syringes. Our finding supports our hypothesis that the efficient transmission of HCV among IDUs may be partly due to the ability of the virus to remain viable in contaminated syringes for prolonged periods. Moreover, we found that HCV survival was dependent on syringe type, time, and temperature. These parameters can be manipulated in the design of public health recommendations and interventions for preventing the spread of HCV among IDUs."
Elijah Paintsil,1,2 Huijie He,3 Christopher Peters,4 Brett D. Lindenbach,4 and Robert Heimer3
Departments of 1Pediatrics, 2Pharmacology, 3Epidemiology and Public Health, and 4Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut
Background.We hypothesized that the high prevalence of hepatitis C virus (HCV) among injection drug users might be due to prolonged virus survival in contaminated syringes.
Methods.We developed a microculture assay to examine the viability of HCV. Syringes were loaded with blood spiked with HCV reporter virus (Jc1/GLuc2A) to simulate 2 scenarios of residual volumes: low void volume (2 μL) for 1‐mL insulin syringes and high void volume (32 μL) for 1‐mL tuberculin syringes. Syringes were stored at 4°C, 22°C, and 37°C for up to 63 days before testing for HCV infectivity by using luciferase activity.
Results.The virus decay rate was biphasic ( h and h). Insulin syringes failed to yield viable HCV beyond day 1 at all storage temperatures except 4°, in which 5% of syringes yielded viable virus on day 7. Tuberculin syringes yielded viable virus from 96%, 71%, and 52% of syringes after storage at 4°, 22°, and 37° for 7 days, respectively, and yielded viable virus up to day 63.
Conclusions.The high prevalence of HCV among injection drug users may be partly due to the resilience of the virus and the syringe type. Our findings may be used to guide prevention strategies.
The global burden of morbidity and mortality from hepatitis C virus (HCV) infection is truly pandemic [1]. There is no vaccine for the prevention of HCV infection, and current therapeutic regimens for HCV infection are limited by efficacy, cost, and treatment adverse effects. Therefore, reduction of risk associated with HCV transmission remains the primary strategy for curbing the HCV epidemic. HCV is transmitted primarily through percutaneous exposure to blood contaminated with HCV. The prevalence of HCV is disproportionately high among injection drug users (IDUs), with seroprevalence as high as 95% [2–11]. The transmission of HCV and human immunodeficiency virus (HIV) among IDUs has been associated with the sharing of equipment used to prepare and administer drugs [12–14]. The prevalence of HCV among IDUs exceeds that of HIV across all seroprevalence studies in many countries. Even in locations in the United States where HIV seroprevalence among IDUs is low (1%–10%), HCV seroprevalence among IDUs is high (30%–85%) [15–18]
HCV incident infections continue to occur at a startling high rate in IDU populations worldwide. It is estimated that the probability of transmission of HCV per exposure to a contaminated syringe is 5‐fold to 20‐fold higher than that of HIV transmission [19–23]. Although harm reduction programs have effectively reduced the incidence of HIV among IDUs, such reductions in incidence have rarely been observed for HCV [8, 24–26]. The difference in transmission between HCV and HIV may be attributed to a higher infectivity of HCV compared with HIV. The biology of HCV transmission, however, has not been well characterized because of the lack of an efficient cell culture and small animal model for assessing HCV replication and infectivity. To date, polymerase chain reaction (PCR)–based assay for detecting viral RNA has been used as a surrogate for infectivity; there is no direct correlation between nucleic acid concentration and viable virus [27].
We hypothesized that the efficient transmission of HCV among IDUs may be partly due to the ability of the virus to remain viable in contaminated syringes for prolonged periods. To test this hypothesis, we developed a microculture assay that allowed us to propagate HCV from small residual volumes contained in the dead space of syringes used by IDUs, and to determine the effects of storage at different temperatures for prolonged periods on the viability of HCV in syringes. We report the results of the first study, to our knowledge, that simulates HCV transmission among IDUs by directly assaying HCV infectivity in syringes.
DISCUSSION
In our experimental simulation of IDU injection practices, we observed that HCV survived in HCV‐contaminated syringes for up to 63 days in high void volume syringes. Our finding supports our hypothesis that the efficient transmission of HCV among IDUs may be partly due to the ability of the virus to remain viable in contaminated syringes for prolonged periods. Moreover, we found that HCV survival was dependent on syringe type, time, and temperature. These parameters can be manipulated in the design of public health recommendations and interventions for preventing the spread of HCV among IDUs.
To our knowledge, this is the first study to establish the survival of HCV in syringes. Until recently, the absence of a sensitive tissue culture assay had made it impossible to develop suitable models to estimate HCV infectivity during the drug injection process. Lindenbach and colleagues [30, 31] recently developed a full‐length HCV genotype 2a infectious clone (HCVcc) that replicates, producing infectious virus in cell culture. To conduct the experiments, we used a genetically modified HCVcc (Jc1/GLuc2A reporter virus) virus that expresses luciferase after viral replication. After infection of Huh‐7.5 cells, the GLuc2A enzyme and infectious reporter virus are released into the culture medium. This allowed us to use the relative luciferase activity to determine HCV infectivity and HCV survival in syringes. Phan et al [29] previously demonstrated that GLuc2A expression was dependent on HCV replication, and Gluc2A expression correlated positively over time with the level of intracellular HCV RNA using quantitative RT‐PCR.
We observed that HCV survival is dependent on the type of syringe; syringes with detachable needles (high void volume) appear far more likely to transmit HCV. This observation is consistent with experimental studies in HIV [36] and epidemiologic studies in HIV and HCV, providing evidence that the probability of transmission is associated with viral burden (ie, a function of viral load and volume of inoculum) [22, 40–42]. In a recent study, Zule et al [41] found an independent association between a history of sharing high void volume syringes and the prevalence of HIV and HCV among IDUs in North Carolina. Interestingly, the investigators likened the protective role played by the use of low void volume syringes to that of male circumcision and antiretroviral therapy in reducing HIV transmission [43, 44]. The type of syringe used by IDUs depends on locality and individual preference. IDUs in the United States predominantly use fixed‐needle insulin syringes (low void syringes); pharmacies no longer sell detachable insulin syringes [40]. In areas where injection practices require volumes of water >1 mL, IDUs frequently resort to the use of syringe volumes >1 mL [41]. Interestingly, syringe exchange programs often stress the importance of providing IDUs with syringes that they prefer and meet their needs [45]. Our finding suggests the use of low void volume syringes should be stressed by syringe exchange programs to reduce HCV transmission.
The infectivity of HCV, in both low and high void volume syringes, declined sharply over the first few days. This was consistent with the observed biphasic decay rate of HCV at room temperature. Our finding of decay in infectivity of extracellular HCV is consistent with previous reports [46]. The survival of HCV in the low void volume syringes had an inverse relation to the storage temperature in many but not all conditions tested. Lower temperatures preserved the viability of HCV in the low void volume syringes to a greater extent than it did in the high void volume syringes. With the high void volume syringes, the infectivity was comparable at all temperatures after the first 14 days of storage. The time course of HCV survival in low void volume syringes is consistent with previous studies with HIV, although HCV appears to survive longer than HIV in high void volume syringes [36]. This raises the question whether the disproportionally high prevalence of HCV in comparison to HIV among IDUs could be partly explained by the differences in survival of these viruses in syringes. HCV has been shown by blood bank services to be stable for at least 7 days in plasma and serum stored at 4°C [47]. Although consistent with our finding of HCV survival in small void volume syringes stored at 4°C, these studies used PCR detection of HCV RNA, which is not a direct demonstration of viable virus. Is it possible that the duration of survival of our laboratory clone differs substantially from the duration of survival of common strains of HCV? Yes, but there is no currently available method to determine this, because there is no tissue culture system that can assess the replication or infectivity of HCV isolates from HCV‐infected individuals. Furthermore, the fact that the prevalence of HCV consistently surpasses that of HIV in IDU populations may be attributed to higher viral titer and a different range of cells susceptible to HCV infection. HIV‐1 requires entry into activated CD4+ cells for productive infection, whereas HCV needs only to enter hepatocytes, which the virus is likely to encounter because injection of HCV‐contaminated drugs brings virus to the liver on its first pass through the circulatory system. Clearly, additional research is needed to elucidate those factors that result in the higher transmissibility of HCV because virus viability alone does not seem to explain this difference.
Interestingly, harm reduction programs have effectively reduced the incidence of HIV but not HCV among IDUs [8, 24–26]. Our findings have implications in the design of public health recommendations for preventing the spread of HCV among IDUs. Successful syringe exchange programs have reduced circulation time of used syringes from 23.5 days to <3 days [26, 39]. Thus, HCV in contaminated syringes may still be viable and hence transmissible throughout the circulation time of syringes found, once syringe exchange programs are established. The types of syringes used by IDUs vary from place to place and usually depend on availability, local preferences, and cultural practices [41]. Although most IDUs in developed countries use low void volume syringes, there are still individuals who prefer high void volume syringes, and syringe exchange programs provide syringes according to an individual’s preference. In some places where homemade drugs are more common (eg, the former Soviet Union), the weaker drug solutions made in this way encourage the use of larger volume syringes that almost invariably come with detachable needles [48]. Because replacing the larger volume syringes is not practical, control of HCV transmission will require substantially expanded access to sterile syringes for IDUs in these regions.
Our study has some limitations. First, the simulation of the survival of HCV in syringes under laboratory‐controlled conditions may not accurately reflect the natural transmission dynamics among IDUs. Second, the data come from the use of a genetically modified HCV laboratory clone derived from a genotype 2a virus. Third, the spiking of HCV‐seronegative blood might not have sufficiently replicated the biological factors (eg, the presence of anti‐HCV antibodies, immune complexes, or cytokines) present in the blood of HCV‐infected individuals that could moderate HCV transmission and infectivity. However, the consistency of our results with previous epidemiologic studies that reported high HCV prevalence among IDUs supports our findings [22, 40–42].
This is the first study to our knowledge to establish the survival of HCV in contaminated syringes and the duration of potential infectiousness. The finding of prolonged duration of survival of HCV in syringes is a public health concern and adds additional evidence of the need for effective syringe exchange programs and other mechanisms to expand syringe access for IDUs.
RESULTS
HCV microculture assay.We developed a microculture assay for investigating the viability of HCV recovered from contaminated syringes. The HCV used (Jc1/Gluc2A) had a luciferase gene from G. princeps inserted between the p7 and NS2 gene [29]. After infection of Huh‐7.5 cells with Jc1/GLuc2A, the GLuc2A enzyme and infectious reporter virus are secreted into the culture medium. HCV replication could be determined over time by measuring secreted GLuc2A activity [29]. This system allowed us to use relative luciferase activity as a function of infectivity or viability of HCV recovered from syringes. Huh‐7.5 cells were infected with HCV reporter virus and incubated for 3 days before culture supernatants were analyzed for luciferase activity.
Assay sensitivity.As a first step, we determined the linear dynamic range of the microculture system. Starting with a viral stock of known TCID50, we prepared serial 1:2 dilutions that were introduced into our system. Negative controls (using HCV‐contaminated blood without cells, uncontaminated blood, or Huh‐7.5 cell alone) yielded uniformly negative results. When 100 μL aliquots of dilution series were introduced, supernatants had relative luciferase activity that showed a strict correlation to expected TCID50 over a linear range of 4 logs, between 1 and 104 TCID50 (Figure 1). This range of sensitivity allowed us to detect changes in infectivity comparable to a >100‐fold reduction in viral load. The limit of detection in the microculture assay was 250 relative luciferase units, equivalent to 0.1 TCID50.
Decay of infectivity of HCV at room temperature.We next investigated the rate of decay of the infectivity of the stock virus at room temperature. Aliquots of the virus were left in room temperature for up to 96 h. Samples were collected at intervals of 6 h and stored at −80°C until the determination of infectivity. We observed a biphasic decay of HCV viability (Figure 2). There was a rapid decline of infectivity within the first 6 h, with a of 0.4 h, followed by a second phase of a relatively slow exponential decay with a of 28 h.
Survival of HCV in syringes.We last investigated the survival of HCV recovered from syringes stored at different temperatures. We simulated 2 scenarios of residual volumes after complete depression of the plunger: low void volume (2 μL) with 1‐mL insulin syringe (with permanently attached needle) and high void volume (32 μL) with 1‐mL tuberculin syringe (with detachable needle). The syringes were loaded with HCV‐contaminated blood and stored at different temperatures for up to 63 days. For each experiment to test for HCV survival, the contents of at least 15 stored syringes for each combination of storage time and temperature were introduced into our assay system. The proportion of HCV‐positive syringes and the infectivity per HCV‐positive syringe were determined. The results presented here came from at least 3 independent experiments.
The low void volume insulin syringes were stored for up to 14 days. We observed an inverse relationship between temperature and HCV survival (Figure 3A). Both the number of HCV‐positive syringes and infectivity of HCV in the positive syringes declined rapidly over time. We recovered viable HCV from syringes stored at 4° for up to 7 days (5% HCV syringes), whereas syringes stored at 22° and 37° yielded no HCV‐positive syringes beyond day 1 of storage. The loss in infectivity of HCV per positive syringe recovered after 1 day of storage at 22° and 37° was 30% and 96%, respectively. After storage at 4°, HCV‐positive syringes showed 38% and 92% reductions in infectivity after 3 and 7 days of storage, respectively (Figure 3B).
The high void volume tuberculin syringes were stored for up to 63 days. In contrast to the results for the low void volume syringes, we observed a prolonged survival of HCV in the high void volume syringes at all storage temperatures; however, as with the low void volume syringes, storage at 4° was more favorable to survival of HCV than was storage at either 22° or 37°. The proportion of syringes with viable HCV declined sharply to 50% over the first 14 days of storage at 22° and 37° (Figure 4A). However, with storage at 4°, we observed a 50% decrease in viable HCV recovery only after 35 days of storage. There was a monotonic decline in the proportion of HCV‐positive syringes stored at 22° (Figure 4A). However, for syringes stored at 4° and 37°, the monotonic decline ceased after day 35. The proportion of HCV‐positive syringes recovered at the final storage duration, 63 days, was 13% at 4°, 20% at 22°, and 6% at 37°.
The infectivity of the HCV recovered from the high void volume syringes was determined as a function of luciferase activity. We observed at least a 90% reduction in infectivity per positive syringe after 1 day of storage at all the temperatures (Figure 4B). The infectivity of recovered virus stored at 4° tended to be higher than at other temperatures over the first 21 days of storage. At the final storage duration, 63 days, the mean infectivity per positive syringe was , , and relative luciferase units for syringes stored at 4°, 22°, and 37°, respectively. Infectivity was therefore significantly higher for syringes harboring viable virus at 4° than at 22° and 37°.
The Journal of Infectious Diseases Sept 15 2010 Early publication
"This is the first study to our knowledge to establish the survival of HCV in contaminated syringes and the duration of potential infectiousness. The finding of prolonged duration of survival of HCV in syringes is a public health concern and adds additional evidence of the need for effective syringe exchange programs and other mechanisms to expand syringe access for IDUs......In our experimental simulation of IDU injection practices, we observed that HCV survived in HCV‐contaminated syringes for up to 63 days in high void volume syringes. Our finding supports our hypothesis that the efficient transmission of HCV among IDUs may be partly due to the ability of the virus to remain viable in contaminated syringes for prolonged periods. Moreover, we found that HCV survival was dependent on syringe type, time, and temperature. These parameters can be manipulated in the design of public health recommendations and interventions for preventing the spread of HCV among IDUs."
Elijah Paintsil,1,2 Huijie He,3 Christopher Peters,4 Brett D. Lindenbach,4 and Robert Heimer3
Departments of 1Pediatrics, 2Pharmacology, 3Epidemiology and Public Health, and 4Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut
Background.We hypothesized that the high prevalence of hepatitis C virus (HCV) among injection drug users might be due to prolonged virus survival in contaminated syringes.
Methods.We developed a microculture assay to examine the viability of HCV. Syringes were loaded with blood spiked with HCV reporter virus (Jc1/GLuc2A) to simulate 2 scenarios of residual volumes: low void volume (2 μL) for 1‐mL insulin syringes and high void volume (32 μL) for 1‐mL tuberculin syringes. Syringes were stored at 4°C, 22°C, and 37°C for up to 63 days before testing for HCV infectivity by using luciferase activity.
Results.The virus decay rate was biphasic ( h and h). Insulin syringes failed to yield viable HCV beyond day 1 at all storage temperatures except 4°, in which 5% of syringes yielded viable virus on day 7. Tuberculin syringes yielded viable virus from 96%, 71%, and 52% of syringes after storage at 4°, 22°, and 37° for 7 days, respectively, and yielded viable virus up to day 63.
Conclusions.The high prevalence of HCV among injection drug users may be partly due to the resilience of the virus and the syringe type. Our findings may be used to guide prevention strategies.
The global burden of morbidity and mortality from hepatitis C virus (HCV) infection is truly pandemic [1]. There is no vaccine for the prevention of HCV infection, and current therapeutic regimens for HCV infection are limited by efficacy, cost, and treatment adverse effects. Therefore, reduction of risk associated with HCV transmission remains the primary strategy for curbing the HCV epidemic. HCV is transmitted primarily through percutaneous exposure to blood contaminated with HCV. The prevalence of HCV is disproportionately high among injection drug users (IDUs), with seroprevalence as high as 95% [2–11]. The transmission of HCV and human immunodeficiency virus (HIV) among IDUs has been associated with the sharing of equipment used to prepare and administer drugs [12–14]. The prevalence of HCV among IDUs exceeds that of HIV across all seroprevalence studies in many countries. Even in locations in the United States where HIV seroprevalence among IDUs is low (1%–10%), HCV seroprevalence among IDUs is high (30%–85%) [15–18]
HCV incident infections continue to occur at a startling high rate in IDU populations worldwide. It is estimated that the probability of transmission of HCV per exposure to a contaminated syringe is 5‐fold to 20‐fold higher than that of HIV transmission [19–23]. Although harm reduction programs have effectively reduced the incidence of HIV among IDUs, such reductions in incidence have rarely been observed for HCV [8, 24–26]. The difference in transmission between HCV and HIV may be attributed to a higher infectivity of HCV compared with HIV. The biology of HCV transmission, however, has not been well characterized because of the lack of an efficient cell culture and small animal model for assessing HCV replication and infectivity. To date, polymerase chain reaction (PCR)–based assay for detecting viral RNA has been used as a surrogate for infectivity; there is no direct correlation between nucleic acid concentration and viable virus [27].
We hypothesized that the efficient transmission of HCV among IDUs may be partly due to the ability of the virus to remain viable in contaminated syringes for prolonged periods. To test this hypothesis, we developed a microculture assay that allowed us to propagate HCV from small residual volumes contained in the dead space of syringes used by IDUs, and to determine the effects of storage at different temperatures for prolonged periods on the viability of HCV in syringes. We report the results of the first study, to our knowledge, that simulates HCV transmission among IDUs by directly assaying HCV infectivity in syringes.
DISCUSSION
In our experimental simulation of IDU injection practices, we observed that HCV survived in HCV‐contaminated syringes for up to 63 days in high void volume syringes. Our finding supports our hypothesis that the efficient transmission of HCV among IDUs may be partly due to the ability of the virus to remain viable in contaminated syringes for prolonged periods. Moreover, we found that HCV survival was dependent on syringe type, time, and temperature. These parameters can be manipulated in the design of public health recommendations and interventions for preventing the spread of HCV among IDUs.
To our knowledge, this is the first study to establish the survival of HCV in syringes. Until recently, the absence of a sensitive tissue culture assay had made it impossible to develop suitable models to estimate HCV infectivity during the drug injection process. Lindenbach and colleagues [30, 31] recently developed a full‐length HCV genotype 2a infectious clone (HCVcc) that replicates, producing infectious virus in cell culture. To conduct the experiments, we used a genetically modified HCVcc (Jc1/GLuc2A reporter virus) virus that expresses luciferase after viral replication. After infection of Huh‐7.5 cells, the GLuc2A enzyme and infectious reporter virus are released into the culture medium. This allowed us to use the relative luciferase activity to determine HCV infectivity and HCV survival in syringes. Phan et al [29] previously demonstrated that GLuc2A expression was dependent on HCV replication, and Gluc2A expression correlated positively over time with the level of intracellular HCV RNA using quantitative RT‐PCR.
We observed that HCV survival is dependent on the type of syringe; syringes with detachable needles (high void volume) appear far more likely to transmit HCV. This observation is consistent with experimental studies in HIV [36] and epidemiologic studies in HIV and HCV, providing evidence that the probability of transmission is associated with viral burden (ie, a function of viral load and volume of inoculum) [22, 40–42]. In a recent study, Zule et al [41] found an independent association between a history of sharing high void volume syringes and the prevalence of HIV and HCV among IDUs in North Carolina. Interestingly, the investigators likened the protective role played by the use of low void volume syringes to that of male circumcision and antiretroviral therapy in reducing HIV transmission [43, 44]. The type of syringe used by IDUs depends on locality and individual preference. IDUs in the United States predominantly use fixed‐needle insulin syringes (low void syringes); pharmacies no longer sell detachable insulin syringes [40]. In areas where injection practices require volumes of water >1 mL, IDUs frequently resort to the use of syringe volumes >1 mL [41]. Interestingly, syringe exchange programs often stress the importance of providing IDUs with syringes that they prefer and meet their needs [45]. Our finding suggests the use of low void volume syringes should be stressed by syringe exchange programs to reduce HCV transmission.
The infectivity of HCV, in both low and high void volume syringes, declined sharply over the first few days. This was consistent with the observed biphasic decay rate of HCV at room temperature. Our finding of decay in infectivity of extracellular HCV is consistent with previous reports [46]. The survival of HCV in the low void volume syringes had an inverse relation to the storage temperature in many but not all conditions tested. Lower temperatures preserved the viability of HCV in the low void volume syringes to a greater extent than it did in the high void volume syringes. With the high void volume syringes, the infectivity was comparable at all temperatures after the first 14 days of storage. The time course of HCV survival in low void volume syringes is consistent with previous studies with HIV, although HCV appears to survive longer than HIV in high void volume syringes [36]. This raises the question whether the disproportionally high prevalence of HCV in comparison to HIV among IDUs could be partly explained by the differences in survival of these viruses in syringes. HCV has been shown by blood bank services to be stable for at least 7 days in plasma and serum stored at 4°C [47]. Although consistent with our finding of HCV survival in small void volume syringes stored at 4°C, these studies used PCR detection of HCV RNA, which is not a direct demonstration of viable virus. Is it possible that the duration of survival of our laboratory clone differs substantially from the duration of survival of common strains of HCV? Yes, but there is no currently available method to determine this, because there is no tissue culture system that can assess the replication or infectivity of HCV isolates from HCV‐infected individuals. Furthermore, the fact that the prevalence of HCV consistently surpasses that of HIV in IDU populations may be attributed to higher viral titer and a different range of cells susceptible to HCV infection. HIV‐1 requires entry into activated CD4+ cells for productive infection, whereas HCV needs only to enter hepatocytes, which the virus is likely to encounter because injection of HCV‐contaminated drugs brings virus to the liver on its first pass through the circulatory system. Clearly, additional research is needed to elucidate those factors that result in the higher transmissibility of HCV because virus viability alone does not seem to explain this difference.
Interestingly, harm reduction programs have effectively reduced the incidence of HIV but not HCV among IDUs [8, 24–26]. Our findings have implications in the design of public health recommendations for preventing the spread of HCV among IDUs. Successful syringe exchange programs have reduced circulation time of used syringes from 23.5 days to <3 days [26, 39]. Thus, HCV in contaminated syringes may still be viable and hence transmissible throughout the circulation time of syringes found, once syringe exchange programs are established. The types of syringes used by IDUs vary from place to place and usually depend on availability, local preferences, and cultural practices [41]. Although most IDUs in developed countries use low void volume syringes, there are still individuals who prefer high void volume syringes, and syringe exchange programs provide syringes according to an individual’s preference. In some places where homemade drugs are more common (eg, the former Soviet Union), the weaker drug solutions made in this way encourage the use of larger volume syringes that almost invariably come with detachable needles [48]. Because replacing the larger volume syringes is not practical, control of HCV transmission will require substantially expanded access to sterile syringes for IDUs in these regions.
Our study has some limitations. First, the simulation of the survival of HCV in syringes under laboratory‐controlled conditions may not accurately reflect the natural transmission dynamics among IDUs. Second, the data come from the use of a genetically modified HCV laboratory clone derived from a genotype 2a virus. Third, the spiking of HCV‐seronegative blood might not have sufficiently replicated the biological factors (eg, the presence of anti‐HCV antibodies, immune complexes, or cytokines) present in the blood of HCV‐infected individuals that could moderate HCV transmission and infectivity. However, the consistency of our results with previous epidemiologic studies that reported high HCV prevalence among IDUs supports our findings [22, 40–42].
This is the first study to our knowledge to establish the survival of HCV in contaminated syringes and the duration of potential infectiousness. The finding of prolonged duration of survival of HCV in syringes is a public health concern and adds additional evidence of the need for effective syringe exchange programs and other mechanisms to expand syringe access for IDUs.
RESULTS
HCV microculture assay.We developed a microculture assay for investigating the viability of HCV recovered from contaminated syringes. The HCV used (Jc1/Gluc2A) had a luciferase gene from G. princeps inserted between the p7 and NS2 gene [29]. After infection of Huh‐7.5 cells with Jc1/GLuc2A, the GLuc2A enzyme and infectious reporter virus are secreted into the culture medium. HCV replication could be determined over time by measuring secreted GLuc2A activity [29]. This system allowed us to use relative luciferase activity as a function of infectivity or viability of HCV recovered from syringes. Huh‐7.5 cells were infected with HCV reporter virus and incubated for 3 days before culture supernatants were analyzed for luciferase activity.
Assay sensitivity.As a first step, we determined the linear dynamic range of the microculture system. Starting with a viral stock of known TCID50, we prepared serial 1:2 dilutions that were introduced into our system. Negative controls (using HCV‐contaminated blood without cells, uncontaminated blood, or Huh‐7.5 cell alone) yielded uniformly negative results. When 100 μL aliquots of dilution series were introduced, supernatants had relative luciferase activity that showed a strict correlation to expected TCID50 over a linear range of 4 logs, between 1 and 104 TCID50 (Figure 1). This range of sensitivity allowed us to detect changes in infectivity comparable to a >100‐fold reduction in viral load. The limit of detection in the microculture assay was 250 relative luciferase units, equivalent to 0.1 TCID50.
Decay of infectivity of HCV at room temperature.We next investigated the rate of decay of the infectivity of the stock virus at room temperature. Aliquots of the virus were left in room temperature for up to 96 h. Samples were collected at intervals of 6 h and stored at −80°C until the determination of infectivity. We observed a biphasic decay of HCV viability (Figure 2). There was a rapid decline of infectivity within the first 6 h, with a of 0.4 h, followed by a second phase of a relatively slow exponential decay with a of 28 h.
Survival of HCV in syringes.We last investigated the survival of HCV recovered from syringes stored at different temperatures. We simulated 2 scenarios of residual volumes after complete depression of the plunger: low void volume (2 μL) with 1‐mL insulin syringe (with permanently attached needle) and high void volume (32 μL) with 1‐mL tuberculin syringe (with detachable needle). The syringes were loaded with HCV‐contaminated blood and stored at different temperatures for up to 63 days. For each experiment to test for HCV survival, the contents of at least 15 stored syringes for each combination of storage time and temperature were introduced into our assay system. The proportion of HCV‐positive syringes and the infectivity per HCV‐positive syringe were determined. The results presented here came from at least 3 independent experiments.
The low void volume insulin syringes were stored for up to 14 days. We observed an inverse relationship between temperature and HCV survival (Figure 3A). Both the number of HCV‐positive syringes and infectivity of HCV in the positive syringes declined rapidly over time. We recovered viable HCV from syringes stored at 4° for up to 7 days (5% HCV syringes), whereas syringes stored at 22° and 37° yielded no HCV‐positive syringes beyond day 1 of storage. The loss in infectivity of HCV per positive syringe recovered after 1 day of storage at 22° and 37° was 30% and 96%, respectively. After storage at 4°, HCV‐positive syringes showed 38% and 92% reductions in infectivity after 3 and 7 days of storage, respectively (Figure 3B).
The high void volume tuberculin syringes were stored for up to 63 days. In contrast to the results for the low void volume syringes, we observed a prolonged survival of HCV in the high void volume syringes at all storage temperatures; however, as with the low void volume syringes, storage at 4° was more favorable to survival of HCV than was storage at either 22° or 37°. The proportion of syringes with viable HCV declined sharply to 50% over the first 14 days of storage at 22° and 37° (Figure 4A). However, with storage at 4°, we observed a 50% decrease in viable HCV recovery only after 35 days of storage. There was a monotonic decline in the proportion of HCV‐positive syringes stored at 22° (Figure 4A). However, for syringes stored at 4° and 37°, the monotonic decline ceased after day 35. The proportion of HCV‐positive syringes recovered at the final storage duration, 63 days, was 13% at 4°, 20% at 22°, and 6% at 37°.
The infectivity of the HCV recovered from the high void volume syringes was determined as a function of luciferase activity. We observed at least a 90% reduction in infectivity per positive syringe after 1 day of storage at all the temperatures (Figure 4B). The infectivity of recovered virus stored at 4° tended to be higher than at other temperatures over the first 21 days of storage. At the final storage duration, 63 days, the mean infectivity per positive syringe was , , and relative luciferase units for syringes stored at 4°, 22°, and 37°, respectively. Infectivity was therefore significantly higher for syringes harboring viable virus at 4° than at 22° and 37°.
ZymoGenetics Announces Completion of Enrollment in Phase 2b Clinical Trial with PEG-Interferon lambda in Hepatitis C
ZymoGenetics Announces Completion of Enrollment in Phase 2b Clinical Trial with PEG-Interferon lambda in Hepatitis C
press release
Aug. 25, 2010
Phase 1b study of pegylated interferon lambda 1 with or without ...
Interferon lambda 1 (IFN-λ1) is a type III IFN that produces intracellular responses similar to those of IFN-α but in fewer cell types because of ...
www.natap.org/2010/HCV/080910_02.htm
A Phase 1b Dose-Ranging Study of 4 Weeks of PEG-Interferon (IFN ...
Nov 3, 2009 ... Background: PEG-IFN-lambda (PEG-IFN-λ) is a unique interferon that has fewer flu -like symptoms and hematologic adverse effects than are ...
www.natap.org/2009/AASLD/AASLD_20.htm
SEATTLE, Aug 25, 2010 (BUSINESS WIRE) -- ZymoGenetics, Inc. today announced enrollment has been completed in the Phase 2b clinical trial with PEG-Interferon lambda and ribavirin in chronic hepatitis C virus (HCV) infection. ZymoGenetics is investigating PEG-Interferon lambda in collaboration with Bristol-Myers Squibb Company for the treatment of HCV infection.
"We're very pleased to have completed the enrollment in the Phase 2b PEG-IFN lambda clinical trial in less than three months," said Eleanor L. Ramos, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. "The rapid enrollment to this study speaks to the motivation and enthusiasm of the clinical trial investigators to help address the unmet medical need in hepatitis C and also to the outstanding execution by our clinical team. We should now be able to assess the primary endpoint earlier than originally projected, and we look forward to assessing the data and planning for Phase 3."
The Phase 2 EMERGE study is an international, randomized multi-center clinical trial with PEG-Interferon lambda and ribavirin in treatment-naive patients with HCV. The Phase 2b study enrolled 570 patients with genotypes 1, 2, 3 and 4 chronic HCV infection. The study is assessing the safety and antiviral efficacy of three doses of PEG-Interferon lambda (120 mcg, 180 mcg and 240 mcg) compared to PEGASYS(R). Weekly subcutaneous doses of PEG-Interferon lambda or PEGASYS are being administered for 48 weeks in genotype 1 and 4 patients and for 24 weeks in genotype 2 and 3 patients. All patients also receive daily ribavirin. The primary endpoint of the trial is the proportion of patients who achieve undetectable levels of HCV RNA after 12 weeks of therapy (complete Early Virological Response). Achievement of Early Virologic Response will also be assessed by patient IL-28B genotype, which has been shown to be a robust predictor of treatment success with the combination of interferon-alpha and ribavirin.
PEG-Interferon lambda
PEG-Interferon lambda (IL-29) is a novel interferon in development for hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons, such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.
About ZymoGenetics
ZymoGenetics is a biopharmaceutical company focused on the development and commercialization of therapeutic proteins for the treatment of human diseases. The company has developed and is marketing RECOTHROM(R) Thrombin, topical (Recombinant) in the United States. ZymoGenetics has two product candidates in Phase 2 clinical development: PEG-Interferon lambda, being studied in collaboration with Bristol-Myers Squibb for treatment of hepatitis C virus (HCV) infection, and IL-21, being tested as a potential treatment for metastatic melanoma. In addition, ZymoGenetics has an anti-IL-31 monoclonal antibody in preclinical development, which it expects to test initially as a treatment for atopic dermatitis. Several of the product candidates previously identified through ZymoGenetics' discovery research efforts have been licensed to and are being developed by third parties, including Merck Serono and Novo Nordisk. ZymoGenetics is eligible to receive milestone payments and royalties related to these assets. For further information, visit www.zymogenetics.com.
ZymoGenetics Forward-Looking Statements
This press release contains forward-looking statements, including statements related to conducting and analyzing the results of clinical trials. Words such as "believes," "should" and "could" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon ZymoGenetics' current expectations and involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to ZymoGenetics' ability to design and conduct clinical trials, the possibility that clinical trial results may vary between different arms of a clinical trial and the difficulty of using prior clinical trial results to predict future outcomes, as well as those other risks detailed in ZymoGenetics' filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2009 and periodic reports on Form 10-Q and current reports on Form 8-K. Do not place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and, except where required by law, ZymoGenetics undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release.
PEGASYS(R) (Peginterferon alfa-2a) is a registered trademark of Hoffman La Roche.
SOURCE: ZymoGenetics, Inc.
ZymoGenetics, Inc.
Susan W. Specht 206-442-6592
press release
Aug. 25, 2010
Phase 1b study of pegylated interferon lambda 1 with or without ...
Interferon lambda 1 (IFN-λ1) is a type III IFN that produces intracellular responses similar to those of IFN-α but in fewer cell types because of ...
www.natap.org/2010/HCV/080910_02.htm
A Phase 1b Dose-Ranging Study of 4 Weeks of PEG-Interferon (IFN ...
Nov 3, 2009 ... Background: PEG-IFN-lambda (PEG-IFN-λ) is a unique interferon that has fewer flu -like symptoms and hematologic adverse effects than are ...
www.natap.org/2009/AASLD/AASLD_20.htm
SEATTLE, Aug 25, 2010 (BUSINESS WIRE) -- ZymoGenetics, Inc. today announced enrollment has been completed in the Phase 2b clinical trial with PEG-Interferon lambda and ribavirin in chronic hepatitis C virus (HCV) infection. ZymoGenetics is investigating PEG-Interferon lambda in collaboration with Bristol-Myers Squibb Company for the treatment of HCV infection.
"We're very pleased to have completed the enrollment in the Phase 2b PEG-IFN lambda clinical trial in less than three months," said Eleanor L. Ramos, M.D., Senior Vice President and Chief Medical Officer of ZymoGenetics. "The rapid enrollment to this study speaks to the motivation and enthusiasm of the clinical trial investigators to help address the unmet medical need in hepatitis C and also to the outstanding execution by our clinical team. We should now be able to assess the primary endpoint earlier than originally projected, and we look forward to assessing the data and planning for Phase 3."
The Phase 2 EMERGE study is an international, randomized multi-center clinical trial with PEG-Interferon lambda and ribavirin in treatment-naive patients with HCV. The Phase 2b study enrolled 570 patients with genotypes 1, 2, 3 and 4 chronic HCV infection. The study is assessing the safety and antiviral efficacy of three doses of PEG-Interferon lambda (120 mcg, 180 mcg and 240 mcg) compared to PEGASYS(R). Weekly subcutaneous doses of PEG-Interferon lambda or PEGASYS are being administered for 48 weeks in genotype 1 and 4 patients and for 24 weeks in genotype 2 and 3 patients. All patients also receive daily ribavirin. The primary endpoint of the trial is the proportion of patients who achieve undetectable levels of HCV RNA after 12 weeks of therapy (complete Early Virological Response). Achievement of Early Virologic Response will also be assessed by patient IL-28B genotype, which has been shown to be a robust predictor of treatment success with the combination of interferon-alpha and ribavirin.
PEG-Interferon lambda
PEG-Interferon lambda (IL-29) is a novel interferon in development for hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons, such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.
About ZymoGenetics
ZymoGenetics is a biopharmaceutical company focused on the development and commercialization of therapeutic proteins for the treatment of human diseases. The company has developed and is marketing RECOTHROM(R) Thrombin, topical (Recombinant) in the United States. ZymoGenetics has two product candidates in Phase 2 clinical development: PEG-Interferon lambda, being studied in collaboration with Bristol-Myers Squibb for treatment of hepatitis C virus (HCV) infection, and IL-21, being tested as a potential treatment for metastatic melanoma. In addition, ZymoGenetics has an anti-IL-31 monoclonal antibody in preclinical development, which it expects to test initially as a treatment for atopic dermatitis. Several of the product candidates previously identified through ZymoGenetics' discovery research efforts have been licensed to and are being developed by third parties, including Merck Serono and Novo Nordisk. ZymoGenetics is eligible to receive milestone payments and royalties related to these assets. For further information, visit www.zymogenetics.com.
ZymoGenetics Forward-Looking Statements
This press release contains forward-looking statements, including statements related to conducting and analyzing the results of clinical trials. Words such as "believes," "should" and "could" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon ZymoGenetics' current expectations and involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to ZymoGenetics' ability to design and conduct clinical trials, the possibility that clinical trial results may vary between different arms of a clinical trial and the difficulty of using prior clinical trial results to predict future outcomes, as well as those other risks detailed in ZymoGenetics' filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2009 and periodic reports on Form 10-Q and current reports on Form 8-K. Do not place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and, except where required by law, ZymoGenetics undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release.
PEGASYS(R) (Peginterferon alfa-2a) is a registered trademark of Hoffman La Roche.
SOURCE: ZymoGenetics, Inc.
ZymoGenetics, Inc.
Susan W. Specht 206-442-6592
Early HCV Treatment?: Chronic and cleared hepatitis C viral infection:
Early HCV Treatment?: Chronic and cleared hepatitis C viral infection:
A nationwide cohort study - pdf attached
Download the PDF here
Jnl of Hepatology July 2010
"Five-year survival was 86% (95% CI: 84-87%) among patients in the chronic HCV group and 92% (95% CI: 91-94%) among those in the cleared HCV group (Fig. 1)...... In HCV RNA positive patients, the 8-year risks of death were: 5.5% from liver-related death, 5.5% from non-liver-related natural death, 8.8% from unnatural death, and 0.8% from other death. In HCV RNA negative patients these estimates were 2.0%, for liver-related death, 5.0% for non-liver-related natural death, 6.6% for unnatural death, and 0.2% for other death (Fig. 2).....Chronic HCV-infection was primarily associated with liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88)"
Lars Haukali Omland1Corresponding Author Informationemail address, Henrik Krarup2, Peter Jepsen3, Jorgen Georgsen4, Lene Holm Harritshoj5, Kirsten Riisom6, Svend Erik Hove Jacobsen7, Per Schouenborg8, Peer Brehm Christensen9, Henrik Toft Sorensen310, Niels Obel1, On behalf of the DANVIR Cohort Study
ABSTRACT
Background & Aims
It is unknown whether mortality differs between patients with chronic hepatitis C virus (HCV) replication and those who cleared the virus after infection. We examined the impact of chronic HCV replication on mortality among Danish patients testing positive for HCV antibodies.
Methods
This nationwide cohort study focused on Danish patients with at least one HCV RNA measurement available after testing positive for HCV antibodies between 1996 and 2005. To capture long-term prognosis, eligible patients needed to be alive 1year after HCV RNA assessment. We estimated mortality rate ratios (MRRs) using Cox regression (for overall mortality) and subdistribution hazard ratios (SDHRs) for cause-specific mortality, controlling for gender, age, comorbidity, calendar period, alcohol abuse, injection drug use, and income.
Results
Of the 6292 patients under study, 63% had chronic HCV-infection and 37% had cleared the virus. Five-year survival was 86% (95% confidence interval (CI): 84-87%) in the chronic HCV group and 92% (95% CI: 91-94%) in the cleared HCV group. Chronic HCV-infection was associated with higher overall mortality (MRR: 1.55, 95% CI: 1.28-1.86) and liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88). Chronic HCV-infection greatly increased the risk of death from primary liver cancer (SDHR: 16.47, 95% CI: 2.24-121.00).
Conclusions
Patients with chronic HCV-infection are at higher risk of death than patients who cleared the infection. The substantial association found between chronic HCV-infection and death from primary liver cancer supports early initiation of antiviral treatment in chronically HCV-infected patients.
Results
From the DANVIR cohort we identified 13,005 patients diagnosed with HCV, of whom 6292 met the studyÕs inclusion criteria. Of these, 3969 patients (63%) were classified as chronically HCV-infected and 2323 (37%) as having cleared the infection. Compared to patients in the cleared group, patients with chronic HCV-infection were more likely to be male, and they also were older and had lower income, more hospitalizations, and a higher prevalence of non-HCV-related liver disease (Table 1).
Overall mortality
During 23,648 person-years of observation (PYR), a total of 601 patients died (MR: 25.4/1000 PYR, 95% CI: 23.5-27.5) with 448 deaths in the chronic group and 153 deaths in the cleared group. Five-year survival was 86% (95% CI: 84-87%) among patients in the chronic HCV group and 92% (95% CI: 91-94%) among those in the cleared HCV group (Fig. 1). The adjusted MRR was 1.55 (95% CI: 1.28-1.86). Chronic HCV-infection was associated with increased mortality in most subgroups, except among patients with severe comorbidity (Table 2). Restricting the cohort to patients whose positive HCV antibody test was confirmed by a 3rd generation diagnostic test prior to HCV RNA measurement (n=2753) did not change the estimated association between chronic HCV-infection and mortality (data not shown).
Specific causes of death
In HCV RNA positive patients, the 8-year risks of death were: 5.5% from liver-related death, 5.5% from non-liver-related natural death, 8.8% from unnatural death, and 0.8% from other death. In HCV RNA negative patients these estimates were 2.0%, for liver-related death, 5.0% for non-liver-related natural death, 6.6% for unnatural death, and 0.2% for other death (Fig. 2). The risk of death other than liver-related death (i.e. non-liver-related death, unnatural death and other death) thereby far exceeded the risk of liver-related death for both HCV RNA positive and negative patients (15.1% vs. 5.5% and 11.8% vs. 2.0%, respectively). The corresponding causes for specific MRs are provided in Supplementary Table 1.
Chronic HCV-infection was primarily associated with liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88), and to some extent with non-liver-related natural causes of death (SDHR: 1.24, 95% CI: 0.91-1.71) and unnatural causes of death (SDHR: 1.28, 95% CI: 0.97-1.69). In the non-liver-related natural death category, none of the detailed causes of death were notably associated with chronic HCV-infection (Table 3). Except for primary liver cancer, there was no substantially increased risk of death due to neoplasms (SDHR: 1.28, 95% CI: 0.65-2.54).
Of the liver-related deaths, death due to alcoholic liver disease was the most frequent (2.3% vs. 1.4% after 8years of follow-up for patients with chronic vs. cleared HCV-infection). Chronic HCV-infection was substantially associated with death from primary liver cancer (SDHR: 16.47, 95% CI: 2.24-121). However, death from primary liver cancer was rather infrequent (28 events vs. 1 event for patients with chronic vs. cleared HCV-infection, corresponding to an 8-year risk of 1.4% in patients with chronic HCV-infection and of 0.0% in patients with cleared HCV-infection) (Fig. 3). There were no deaths due to oesophageal or gastric varices.
Discussion
We observed an increased mortality among patients with chronic HCV-infection compared to patients with cleared infection, based on HCV RNA testing. This effect was observed in all patient subgroups except in those with severe comorbidity. Chronic HCV-infection was associated with liver-related mortality, and in particular death from primary liver cancer. However, the risk of deaths other than liver-related deaths by far exceeded the risk of liver-related deaths in both HCV RNA positive and HCV RNA negative patients. To our knowledge, no previous study has addressed the impact of chronic HCV replication on mortality in an equivalent nationwide setting with a long and complete follow-up and with an extensive control of confounders.
Our study has several limitations. We had access to the exact date of HCV diagnosis, but not the date of HCV-infection [6]. For a substantial proportion of study participants, HCV-infection could have preceded study inclusion by several years, since most HCV-infections occur subclinically [6]. Thus patients in the chronic group could have had more liver damage at the time of study inclusion than patients in the cleared group. We did not have access to liver biopsies or liver function tests, so we could not directly address this question. More patients in the chronic HCV group than in the cleared group were diagnosed with liver diseases other than HCV. However, we were able to demonstrate that chronic HCV-infection was associated with mortality in patients both with and without pre-existing liver diseases, which indicates that severity of liver disease did not explain our findings. Our analyses did not account for spontaneous or treatment-related viral clearance nor HCV re-infection during follow-up. Most patients are IDUs, and probably as a result, regular testing for HCV RNA subsequent to an initial diagnosis is not performed systematically in Denmark. Modelling HCV viraemia as a time-updated variable thus was not possible in this study. However, spontaneous clearance of HCV-infection subsequent to the initial acute phase of the disease occurs infrequently [25] and only a minority of Danish patients receive antiviral treatment [11]. Finally, despite the large study population and long-term follow up, our study had too small power to make statistically significant estimates for most of the detailed categories of causes of death.
Patients with chronic HCV-infection were at an increased risk of liver-related death, with the strongest association observed between chronic HCV-infection and primary liver cancer. This information is important, and suggests that clearance of the virus almost eliminates the risk of developing primary liver cancer, thus confirming the potential benefit of antiviral treatment. However, one patient in the cleared group developed primary liver cancer. This observation agrees with recent findings of cases of hepatocellular carcinoma in long-term viral suppression responders [26]. These data suggest that clearance of the virus substantially decreases but not fully eliminates the risk of primary liver cancer. Chronic HCV-infection was also associated with other liver-related causes of death (viral hepatitis, alcoholic liver disease and non-alcoholic liver disease), also emphasising the potential for antiviral treatment.
The associations between chronic HCV-infection and non-liver-related natural deaths, unnatural deaths and other deaths diminished when we adjusted for confounders. However, we cannot exclude the possibility of unmeasured or residual confounding. The fact that patients with chronic HCV-infection were at increased risk of unnatural deaths (and to some extent death due to infections) indicates certain risk-taking behaviour in this group. As we were unable to adjust for this factor in our models, this could have resulted in unmeasured confounding. We find it likely that the associations found between chronic HCV-infection and non-liver-related natural deaths, unnatural deaths, and other deaths result from unmeasured confounding. In particular, from more injection drug use among chronically HCV-infected patients than among patients who cleared the virus.
The Trent HCV Cohort Study examined predictors of survival among HCV-infected patients treated in secondary care centres. That study, unlike ours, reported no substantial association between HCV RNA positive status (compared to HCV RNA negative status) and an increased all-cause mortality (MRR: 1.1, 95% CI 0.7-1.8) [5]. These inconsistent findings might be a result of lack of precision in the Trent study, which included only 157 deaths in the HCV RNA positive group and 21 deaths in the HCV negative group. More likely, however, these inconsistencies stem from differences in the study populations, as the Trent HCV Cohort only included patients from referral sites, while our study included nearly all patients tested for HCV RNA in Denmark. The patients in the Trent study therefore may have been at a more advanced stage of their liver disease and may have had more comorbidity. In that case, results for the Trent HCV Cohort should be compared to results for the most diseased subgroup of our study population. In fact, we did not observe a substantial impact of chronic HCV-infection among patients with a high comorbidity index, those with alcohol abuse or those who had been hospitalized recently. In a previous study from our group focusing on Danish HIV-infected IDUs with a high level of comorbidity, we also observed no association between chronic vs. cleared HCV-infection and mortality [27]. These findings suggest that chronic HCV-infection, compared to cleared HCV-infection, is associated with increased mortality in most patient groups. However, in high-risk study populations characterised by substantial mortality, the relative impact of chronic HCV-infection is limited.
We conclude that based on HCV RNA assessment, patients with chronic HCV-infection have higher mortality and, in particular, a higher risk of liver-related death than patients who cleared the virus. The pronounced association between chronic HCV-infection and death from primary liver cancer provides a rationale for antiviral treatment in chronically HCV-infected patients. However, our data also underline the importance of a balanced decision, as subgroups characterised by substantial mortality probably have less potential for a treatment benefit.
A nationwide cohort study - pdf attached
Download the PDF here
Jnl of Hepatology July 2010
"Five-year survival was 86% (95% CI: 84-87%) among patients in the chronic HCV group and 92% (95% CI: 91-94%) among those in the cleared HCV group (Fig. 1)...... In HCV RNA positive patients, the 8-year risks of death were: 5.5% from liver-related death, 5.5% from non-liver-related natural death, 8.8% from unnatural death, and 0.8% from other death. In HCV RNA negative patients these estimates were 2.0%, for liver-related death, 5.0% for non-liver-related natural death, 6.6% for unnatural death, and 0.2% for other death (Fig. 2).....Chronic HCV-infection was primarily associated with liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88)"
Lars Haukali Omland1Corresponding Author Informationemail address, Henrik Krarup2, Peter Jepsen3, Jorgen Georgsen4, Lene Holm Harritshoj5, Kirsten Riisom6, Svend Erik Hove Jacobsen7, Per Schouenborg8, Peer Brehm Christensen9, Henrik Toft Sorensen310, Niels Obel1, On behalf of the DANVIR Cohort Study
ABSTRACT
Background & Aims
It is unknown whether mortality differs between patients with chronic hepatitis C virus (HCV) replication and those who cleared the virus after infection. We examined the impact of chronic HCV replication on mortality among Danish patients testing positive for HCV antibodies.
Methods
This nationwide cohort study focused on Danish patients with at least one HCV RNA measurement available after testing positive for HCV antibodies between 1996 and 2005. To capture long-term prognosis, eligible patients needed to be alive 1year after HCV RNA assessment. We estimated mortality rate ratios (MRRs) using Cox regression (for overall mortality) and subdistribution hazard ratios (SDHRs) for cause-specific mortality, controlling for gender, age, comorbidity, calendar period, alcohol abuse, injection drug use, and income.
Results
Of the 6292 patients under study, 63% had chronic HCV-infection and 37% had cleared the virus. Five-year survival was 86% (95% confidence interval (CI): 84-87%) in the chronic HCV group and 92% (95% CI: 91-94%) in the cleared HCV group. Chronic HCV-infection was associated with higher overall mortality (MRR: 1.55, 95% CI: 1.28-1.86) and liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88). Chronic HCV-infection greatly increased the risk of death from primary liver cancer (SDHR: 16.47, 95% CI: 2.24-121.00).
Conclusions
Patients with chronic HCV-infection are at higher risk of death than patients who cleared the infection. The substantial association found between chronic HCV-infection and death from primary liver cancer supports early initiation of antiviral treatment in chronically HCV-infected patients.
Results
From the DANVIR cohort we identified 13,005 patients diagnosed with HCV, of whom 6292 met the studyÕs inclusion criteria. Of these, 3969 patients (63%) were classified as chronically HCV-infected and 2323 (37%) as having cleared the infection. Compared to patients in the cleared group, patients with chronic HCV-infection were more likely to be male, and they also were older and had lower income, more hospitalizations, and a higher prevalence of non-HCV-related liver disease (Table 1).
Overall mortality
During 23,648 person-years of observation (PYR), a total of 601 patients died (MR: 25.4/1000 PYR, 95% CI: 23.5-27.5) with 448 deaths in the chronic group and 153 deaths in the cleared group. Five-year survival was 86% (95% CI: 84-87%) among patients in the chronic HCV group and 92% (95% CI: 91-94%) among those in the cleared HCV group (Fig. 1). The adjusted MRR was 1.55 (95% CI: 1.28-1.86). Chronic HCV-infection was associated with increased mortality in most subgroups, except among patients with severe comorbidity (Table 2). Restricting the cohort to patients whose positive HCV antibody test was confirmed by a 3rd generation diagnostic test prior to HCV RNA measurement (n=2753) did not change the estimated association between chronic HCV-infection and mortality (data not shown).
Specific causes of death
In HCV RNA positive patients, the 8-year risks of death were: 5.5% from liver-related death, 5.5% from non-liver-related natural death, 8.8% from unnatural death, and 0.8% from other death. In HCV RNA negative patients these estimates were 2.0%, for liver-related death, 5.0% for non-liver-related natural death, 6.6% for unnatural death, and 0.2% for other death (Fig. 2). The risk of death other than liver-related death (i.e. non-liver-related death, unnatural death and other death) thereby far exceeded the risk of liver-related death for both HCV RNA positive and negative patients (15.1% vs. 5.5% and 11.8% vs. 2.0%, respectively). The corresponding causes for specific MRs are provided in Supplementary Table 1.
Chronic HCV-infection was primarily associated with liver-related death (SDHR: 2.42, 95% CI: 1.51-3.88), and to some extent with non-liver-related natural causes of death (SDHR: 1.24, 95% CI: 0.91-1.71) and unnatural causes of death (SDHR: 1.28, 95% CI: 0.97-1.69). In the non-liver-related natural death category, none of the detailed causes of death were notably associated with chronic HCV-infection (Table 3). Except for primary liver cancer, there was no substantially increased risk of death due to neoplasms (SDHR: 1.28, 95% CI: 0.65-2.54).
Of the liver-related deaths, death due to alcoholic liver disease was the most frequent (2.3% vs. 1.4% after 8years of follow-up for patients with chronic vs. cleared HCV-infection). Chronic HCV-infection was substantially associated with death from primary liver cancer (SDHR: 16.47, 95% CI: 2.24-121). However, death from primary liver cancer was rather infrequent (28 events vs. 1 event for patients with chronic vs. cleared HCV-infection, corresponding to an 8-year risk of 1.4% in patients with chronic HCV-infection and of 0.0% in patients with cleared HCV-infection) (Fig. 3). There were no deaths due to oesophageal or gastric varices.
Discussion
We observed an increased mortality among patients with chronic HCV-infection compared to patients with cleared infection, based on HCV RNA testing. This effect was observed in all patient subgroups except in those with severe comorbidity. Chronic HCV-infection was associated with liver-related mortality, and in particular death from primary liver cancer. However, the risk of deaths other than liver-related deaths by far exceeded the risk of liver-related deaths in both HCV RNA positive and HCV RNA negative patients. To our knowledge, no previous study has addressed the impact of chronic HCV replication on mortality in an equivalent nationwide setting with a long and complete follow-up and with an extensive control of confounders.
Our study has several limitations. We had access to the exact date of HCV diagnosis, but not the date of HCV-infection [6]. For a substantial proportion of study participants, HCV-infection could have preceded study inclusion by several years, since most HCV-infections occur subclinically [6]. Thus patients in the chronic group could have had more liver damage at the time of study inclusion than patients in the cleared group. We did not have access to liver biopsies or liver function tests, so we could not directly address this question. More patients in the chronic HCV group than in the cleared group were diagnosed with liver diseases other than HCV. However, we were able to demonstrate that chronic HCV-infection was associated with mortality in patients both with and without pre-existing liver diseases, which indicates that severity of liver disease did not explain our findings. Our analyses did not account for spontaneous or treatment-related viral clearance nor HCV re-infection during follow-up. Most patients are IDUs, and probably as a result, regular testing for HCV RNA subsequent to an initial diagnosis is not performed systematically in Denmark. Modelling HCV viraemia as a time-updated variable thus was not possible in this study. However, spontaneous clearance of HCV-infection subsequent to the initial acute phase of the disease occurs infrequently [25] and only a minority of Danish patients receive antiviral treatment [11]. Finally, despite the large study population and long-term follow up, our study had too small power to make statistically significant estimates for most of the detailed categories of causes of death.
Patients with chronic HCV-infection were at an increased risk of liver-related death, with the strongest association observed between chronic HCV-infection and primary liver cancer. This information is important, and suggests that clearance of the virus almost eliminates the risk of developing primary liver cancer, thus confirming the potential benefit of antiviral treatment. However, one patient in the cleared group developed primary liver cancer. This observation agrees with recent findings of cases of hepatocellular carcinoma in long-term viral suppression responders [26]. These data suggest that clearance of the virus substantially decreases but not fully eliminates the risk of primary liver cancer. Chronic HCV-infection was also associated with other liver-related causes of death (viral hepatitis, alcoholic liver disease and non-alcoholic liver disease), also emphasising the potential for antiviral treatment.
The associations between chronic HCV-infection and non-liver-related natural deaths, unnatural deaths and other deaths diminished when we adjusted for confounders. However, we cannot exclude the possibility of unmeasured or residual confounding. The fact that patients with chronic HCV-infection were at increased risk of unnatural deaths (and to some extent death due to infections) indicates certain risk-taking behaviour in this group. As we were unable to adjust for this factor in our models, this could have resulted in unmeasured confounding. We find it likely that the associations found between chronic HCV-infection and non-liver-related natural deaths, unnatural deaths, and other deaths result from unmeasured confounding. In particular, from more injection drug use among chronically HCV-infected patients than among patients who cleared the virus.
The Trent HCV Cohort Study examined predictors of survival among HCV-infected patients treated in secondary care centres. That study, unlike ours, reported no substantial association between HCV RNA positive status (compared to HCV RNA negative status) and an increased all-cause mortality (MRR: 1.1, 95% CI 0.7-1.8) [5]. These inconsistent findings might be a result of lack of precision in the Trent study, which included only 157 deaths in the HCV RNA positive group and 21 deaths in the HCV negative group. More likely, however, these inconsistencies stem from differences in the study populations, as the Trent HCV Cohort only included patients from referral sites, while our study included nearly all patients tested for HCV RNA in Denmark. The patients in the Trent study therefore may have been at a more advanced stage of their liver disease and may have had more comorbidity. In that case, results for the Trent HCV Cohort should be compared to results for the most diseased subgroup of our study population. In fact, we did not observe a substantial impact of chronic HCV-infection among patients with a high comorbidity index, those with alcohol abuse or those who had been hospitalized recently. In a previous study from our group focusing on Danish HIV-infected IDUs with a high level of comorbidity, we also observed no association between chronic vs. cleared HCV-infection and mortality [27]. These findings suggest that chronic HCV-infection, compared to cleared HCV-infection, is associated with increased mortality in most patient groups. However, in high-risk study populations characterised by substantial mortality, the relative impact of chronic HCV-infection is limited.
We conclude that based on HCV RNA assessment, patients with chronic HCV-infection have higher mortality and, in particular, a higher risk of liver-related death than patients who cleared the virus. The pronounced association between chronic HCV-infection and death from primary liver cancer provides a rationale for antiviral treatment in chronically HCV-infected patients. However, our data also underline the importance of a balanced decision, as subgroups characterised by substantial mortality probably have less potential for a treatment benefit.
Pharmasset initiates Phase 2b with PSI-7977 in HCV GT 1,2,3 To: Richard Smith
Richard Smith
Date: Tue, Aug 24, 2010 at 7:05 AM
Subject: Pharmasset initiates Phase 2b with PSI-7977 in HCV GT 1,2,3
To: Richard Smith
Good morning,
Attached and pasted below is a press release we issued this morning announcing the start of a Phase 2b trial with PSI-7977 in hepatitis C patients with genotypes 1,2 or 3. While most HCV trials are focusing on genotype 1 HCV, because of the mechanism of action of PSI-7977, a nucleotide analog inhibitor, we are able to also investigate its use in genotype 2 and 3. In these patients we are investigating a shorter treatment regimen (12 weeks versus usual 24 to 48 weeks). Please feel free to call with any questions.
Best,
Richard
609 865 0693 (c)
Pharmasset Initiates Phase 2b Clinical Trial of PSI-7977 for Chronic Hepatitis C Genotypes 1, 2, and 3
- Phase 2b response-guided study in patients with genotype 1 HCV to receive PSI-7977 200mg QD and 400mg QD in combination with pegylated interferon and ribavirin
- Genotype 2 and 3 patients will be enrolled in an open label arm investigating 12 weeks of PSI-7977 400mg QD plus pegylated interferon and ribavirin
- Interim Phase 2b data expected in first half of 2011
PRINCETON, NJ – (Aug 24, 2010) – Pharmasset, Inc. (Nasdaq: VRUS) announced today that dosing has begun in a Phase 2b study of PSI-7977, a nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 200mg QD and 400mg QD in combination with pegylated interferon alfa 2a and ribavirin, the current standard of care (SOC) in patients with HCV genotype 1 who have not been treated previously.
“We look for the Phase 2b to further support the efficacy, safety and resistance profile of PSI-7977 over 12 weeks, and to confirm a dose for continued development,” stated Michelle Berrey, MD, MPH, Pharmasset’s Chief Medical Officer. “Given the potent antiviral activity observed in the Phase 2a study and in vitro evidence for pan-genotype activity, we have also decided to include an exploratory, open label arm of patients with HCV genotype 2 and 3 who will receive a 12 week treatment regimen of PSI-7977 in combination with pegylated interferon and ribavirin. If successful, this shorter treatment regimen would be a first step toward defining a new treatment option for these patients.”
About the Phase 2b Trial
The Phase 2b trial is anticipated to enroll approximately 125 patients infected with HCV genotype 1 who have not been treated previously. The primary endpoint of the trial will be the assessment of safety and tolerability of PSI-7977, in combination with SOC over 12 weeks with response-guided therapy allowing discontinuation of SOC at week 24. The trial will be conducted in the U.S. Patients will be randomized (2:2:1) into one of 3 arms:
-- PSI-7977 200mg QD in combination with SOC for 12 weeks, followed by 12 or 36 weeks of SOC;
-- PSI-7977 400mg QD in combination with SOC for 12 weeks, followed by 12 or 36 weeks of SOC;
-- A control arm of matching placebo with SOC for 48 weeks.
Patients receiving PSI-7977 will discontinue treatment at week 24 if they achieve an extended RVR (eRVR), defined as HCV RNA below the limit of detection (<15 IU/ml) at week 4 and maintained until week 12. Patients who do not achieve an eRVR and all patients on placebo/SOC will continue on standard of care until week 48. Patients will be stratified by IL28B status to ensure balance across cohorts.
In addition, approximately 25 treatment-naïve patients with HCV genotype 2 or 3 will be enrolled in a fourth, open label arm, receiving PSI-7977 400mg QD with SOC for 12 weeks, with no SOC follow-up. Patients will be followed for an additional 24 weeks after discontinuation of all therapy to assess SVR.
Pharmasset anticipates reporting interim data from this trial in the first half of 2011.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently initiated 12 weeks of dosing in a Phase 2b study, and PSI-938, an unpartnered guanosine nucleotide analog in a Phase 1 study. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development. Racivir, for the treatment of HIV, has completed a Phase 2 clinical study.
Pegasys® and Copegus® are registered trademarks of Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
richard.smith@pharmasset.com
Office: +1 (609) 613-4181
Forward-Looking Statements
Pharmasset “Safe Harbor” Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are “forward-looking statements,” including, without limitation, statements that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2009 and our Quarterly Reports on Form 10-Q for the periods ended December 31, 2009, March 31, 2010 and June 30, 2010 filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
Date: Tue, Aug 24, 2010 at 7:05 AM
Subject: Pharmasset initiates Phase 2b with PSI-7977 in HCV GT 1,2,3
To: Richard Smith
Good morning,
Attached and pasted below is a press release we issued this morning announcing the start of a Phase 2b trial with PSI-7977 in hepatitis C patients with genotypes 1,2 or 3. While most HCV trials are focusing on genotype 1 HCV, because of the mechanism of action of PSI-7977, a nucleotide analog inhibitor, we are able to also investigate its use in genotype 2 and 3. In these patients we are investigating a shorter treatment regimen (12 weeks versus usual 24 to 48 weeks). Please feel free to call with any questions.
Best,
Richard
609 865 0693 (c)
Pharmasset Initiates Phase 2b Clinical Trial of PSI-7977 for Chronic Hepatitis C Genotypes 1, 2, and 3
- Phase 2b response-guided study in patients with genotype 1 HCV to receive PSI-7977 200mg QD and 400mg QD in combination with pegylated interferon and ribavirin
- Genotype 2 and 3 patients will be enrolled in an open label arm investigating 12 weeks of PSI-7977 400mg QD plus pegylated interferon and ribavirin
- Interim Phase 2b data expected in first half of 2011
PRINCETON, NJ – (Aug 24, 2010) – Pharmasset, Inc. (Nasdaq: VRUS) announced today that dosing has begun in a Phase 2b study of PSI-7977, a nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 200mg QD and 400mg QD in combination with pegylated interferon alfa 2a and ribavirin, the current standard of care (SOC) in patients with HCV genotype 1 who have not been treated previously.
“We look for the Phase 2b to further support the efficacy, safety and resistance profile of PSI-7977 over 12 weeks, and to confirm a dose for continued development,” stated Michelle Berrey, MD, MPH, Pharmasset’s Chief Medical Officer. “Given the potent antiviral activity observed in the Phase 2a study and in vitro evidence for pan-genotype activity, we have also decided to include an exploratory, open label arm of patients with HCV genotype 2 and 3 who will receive a 12 week treatment regimen of PSI-7977 in combination with pegylated interferon and ribavirin. If successful, this shorter treatment regimen would be a first step toward defining a new treatment option for these patients.”
About the Phase 2b Trial
The Phase 2b trial is anticipated to enroll approximately 125 patients infected with HCV genotype 1 who have not been treated previously. The primary endpoint of the trial will be the assessment of safety and tolerability of PSI-7977, in combination with SOC over 12 weeks with response-guided therapy allowing discontinuation of SOC at week 24. The trial will be conducted in the U.S. Patients will be randomized (2:2:1) into one of 3 arms:
-- PSI-7977 200mg QD in combination with SOC for 12 weeks, followed by 12 or 36 weeks of SOC;
-- PSI-7977 400mg QD in combination with SOC for 12 weeks, followed by 12 or 36 weeks of SOC;
-- A control arm of matching placebo with SOC for 48 weeks.
Patients receiving PSI-7977 will discontinue treatment at week 24 if they achieve an extended RVR (eRVR), defined as HCV RNA below the limit of detection (<15 IU/ml) at week 4 and maintained until week 12. Patients who do not achieve an eRVR and all patients on placebo/SOC will continue on standard of care until week 48. Patients will be stratified by IL28B status to ensure balance across cohorts.
In addition, approximately 25 treatment-naïve patients with HCV genotype 2 or 3 will be enrolled in a fourth, open label arm, receiving PSI-7977 400mg QD with SOC for 12 weeks, with no SOC follow-up. Patients will be followed for an additional 24 weeks after discontinuation of all therapy to assess SVR.
Pharmasset anticipates reporting interim data from this trial in the first half of 2011.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently initiated 12 weeks of dosing in a Phase 2b study, and PSI-938, an unpartnered guanosine nucleotide analog in a Phase 1 study. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development. Racivir, for the treatment of HIV, has completed a Phase 2 clinical study.
Pegasys® and Copegus® are registered trademarks of Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
richard.smith@pharmasset.com
Office: +1 (609) 613-4181
Forward-Looking Statements
Pharmasset “Safe Harbor” Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are “forward-looking statements,” including, without limitation, statements that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2009 and our Quarterly Reports on Form 10-Q for the periods ended December 31, 2009, March 31, 2010 and June 30, 2010 filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
Pharmacy hepatitis tests “could save thousands of lives”
Pharmacy hepatitis tests “could save thousands of lives”
pharmatimes.com
AUGUST 24, 2010
LYNNE TAYLOR
More than half a million people in the UK are estimated to be living with undiagnosed hepatitis B and C, and campaigners say the introduction of testing services in pharmacies could save thousands of lives.
Last year, a viral hepatitis testing pilot project in 19 pharmacies across the nation found a hepatitis B or C positive patient in every six tests conducted. Across the pharmacies, a total of 234 tests were conducted, diagnosing 35 people with hepatitis C (15% of tests) and four people with hepatitis B (2% of tests). This is a far higher proportion of hepatitis C-positive diagnoses than found in GP surgeries, where 4% of tests find positive hepatitis C patients and 2% of tests find hepatitis B patients, says the Hepatitis C Trust which is, with the support of the Royal Pharmaceutical Society of Great Britain, calling for free testing to be introduced in pharmacies.
“It is a tragedy that increasing numbers of people with hepatitis B and C are dying, often from particularly unpleasant liver cancer which these viruses can cause,” says the Trust?s chief executive, Charles Gore. “It is a tragedy because they have generally been living with the virus for years and could have been given treatment at any point, if only they had been diagnosed. So we desperately need new approaches to testing that will find the undiagnosed patients and this pilot study shows pharmacy testing could be just what is needed.”
Call for pilot roll out by PCTs
“If the pharmacy testing pilot is taken as a model and rolled out by PCTs and pharmacies nationally, we can stop people dying needlessly,” he adds.
The pilot programme has ended, but the Isle of Wight continues to offer the tests and has also extended the scheme to include HIV and syphilis tests from the same sample as the viral hepatitis screen.
“This scheme has woken a lot of people up to the problem of viral hepatitis and we are now working with local drug and addiction services in a more integrated way than ever before,” says pharmacist Gary Warner of Regent Pharmacy on the Island. “The results speak for themselves - pharmacies see a different cohort of people to those who see their GP and therefore we can access and diagnose people who otherwise would not have been tested. As an example, the patient that was screened as HIV positive was not someone who would have accessed the test in any other way,” he adds.
The Hepatitis C Trust, supported by the Department of Health, is offering free training to primary care trusts and pharmacists where local services can provide funding for the tests.
According to the Health Protection Agency, there are around 250,000 hepatitis-C positive people in the UK - although some estimates put this number as high as 466,000 - and only around 70,000 people in England and Wales have been diagnosed. The HPA also puts the number of people in the UK living with hepatitis B at 180,000, but the Hepatitis B Foundation estimates that, due to recent immigration trends, this figure is actually 320,000.
pharmatimes.com
AUGUST 24, 2010
LYNNE TAYLOR
More than half a million people in the UK are estimated to be living with undiagnosed hepatitis B and C, and campaigners say the introduction of testing services in pharmacies could save thousands of lives.
Last year, a viral hepatitis testing pilot project in 19 pharmacies across the nation found a hepatitis B or C positive patient in every six tests conducted. Across the pharmacies, a total of 234 tests were conducted, diagnosing 35 people with hepatitis C (15% of tests) and four people with hepatitis B (2% of tests). This is a far higher proportion of hepatitis C-positive diagnoses than found in GP surgeries, where 4% of tests find positive hepatitis C patients and 2% of tests find hepatitis B patients, says the Hepatitis C Trust which is, with the support of the Royal Pharmaceutical Society of Great Britain, calling for free testing to be introduced in pharmacies.
“It is a tragedy that increasing numbers of people with hepatitis B and C are dying, often from particularly unpleasant liver cancer which these viruses can cause,” says the Trust?s chief executive, Charles Gore. “It is a tragedy because they have generally been living with the virus for years and could have been given treatment at any point, if only they had been diagnosed. So we desperately need new approaches to testing that will find the undiagnosed patients and this pilot study shows pharmacy testing could be just what is needed.”
Call for pilot roll out by PCTs
“If the pharmacy testing pilot is taken as a model and rolled out by PCTs and pharmacies nationally, we can stop people dying needlessly,” he adds.
The pilot programme has ended, but the Isle of Wight continues to offer the tests and has also extended the scheme to include HIV and syphilis tests from the same sample as the viral hepatitis screen.
“This scheme has woken a lot of people up to the problem of viral hepatitis and we are now working with local drug and addiction services in a more integrated way than ever before,” says pharmacist Gary Warner of Regent Pharmacy on the Island. “The results speak for themselves - pharmacies see a different cohort of people to those who see their GP and therefore we can access and diagnose people who otherwise would not have been tested. As an example, the patient that was screened as HIV positive was not someone who would have accessed the test in any other way,” he adds.
The Hepatitis C Trust, supported by the Department of Health, is offering free training to primary care trusts and pharmacists where local services can provide funding for the tests.
According to the Health Protection Agency, there are around 250,000 hepatitis-C positive people in the UK - although some estimates put this number as high as 466,000 - and only around 70,000 people in England and Wales have been diagnosed. The HPA also puts the number of people in the UK living with hepatitis B at 180,000, but the Hepatitis B Foundation estimates that, due to recent immigration trends, this figure is actually 320,000.
Subscribe to:
Posts (Atom)
.JPG)